CN105777539B - One kind 2 [2（2,4 difluorophenyls）Pi-allyl] 1,3 diethyl malonates synthetic method - Google Patents
One kind 2 [2（2,4 difluorophenyls）Pi-allyl] 1,3 diethyl malonates synthetic method Download PDFInfo
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- CN105777539B CN105777539B CN201610190074.5A CN201610190074A CN105777539B CN 105777539 B CN105777539 B CN 105777539B CN 201610190074 A CN201610190074 A CN 201610190074A CN 105777539 B CN105777539 B CN 105777539B
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- difluorophenyl
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- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
A kind of synthetic method of 2 [2 (2,4 difluorophenyl) pi-allyl] 1,3 diethyl malonates, it is characterised in that：Step includes：(1) by 2 chloromethyl expoxy propane and 1, the mixing of 3 difluorobenzenes, reacted in the presence of catalyst, obtain the propyl alcohol of 2 (2,4 difluorophenyl) 1 chlorine 3；(2) step (1) is obtained into the propyl alcohol of 2 (2,4 difluorophenyl) 1 chlorine 3 and potassium acid sulfate and chlorobenzene hybrid reaction, obtains 1 (1 chloromethyl vinyl base) 2,4 difluorobenzenes；(3) 1 (the 1 chloromethyl vinyl base) 2 for obtaining step (2), 4 difluorobenzenes are reacted with diethyl malonate, obtain target product 2 [2 (2,4 difluorophenyl) pi-allyl] 1,3 diethyl malonates；Specifically synthesis path is：
Description
Technical field
The present invention relates to the synthetic method of posaconazole intermediate, and in particular to a kind of 2- [2- (2,4- difluorophenyl) alkene
Propyl group] -1,3- diethyl malonates synthetic method.
Background technology
Posaconazole (chemical name：4- [4- [4- [4- [[(3R, 5R) -5- (2,4 difluorobenzene base) -5- (1,2,4- triazoles -
1- ylmethyls) penta ring -3- bases of oxa-] methoxyl group] phenyl] piperazine -1- bases] phenyl] -2- [the amyl- 3- yls of (2S, 3S) -2- hydroxyls] -
1,2,4- triazole -3- ketone, English name：Posaconazole), structural formula is as follows：
Developed by Schering Plough company of the U.S., the U.S. FDA of in September, 2006 approval listing, is a kind of highly lipophilic wide spectrum three
Triazole antifungal agent.Trade name Noxafil (promise section flies), oral suspensions, it is mainly used in preventing 13 years old and above patient
Intrusive mood Aspergillus and monilial infection, and treatment pars oralis pharyngis monilial infection and to Fluconazole and the mouth of voriconazole resistance
Pharyngeal monilial infection.
2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates are the intermediates for synthesizing posaconazole, its
Structural formula is as follows：
European patent EP 2789610 (A1), world patent WO 2011144653 (A1), WO 2011144656 (A1) with
It is as follows and WO 2011144657 (A1) discloses the method that the intermediate is synthesized by 1,3- difluorobenzenes：
The above method will use expensive trimethyl chloromethyl base silane class material, cause 2- [2- (2,4- difluorobenzenes
Base) pi-allyl] -1,3- diethyl malonate production cost height significantly raises.In addition, also used in what is more important this method
To grignard reaction, the reaction needs anhydrous and oxygen-free condition, it is difficult to operates, is not easy to realize industrialized production；In addition, the course of reaction
The compound chloracetyl chloride of intense irritation is also used, pollution is larger, and has a strong impact on the health of experimenter.
The content of the invention
The present invention is directed to above-mentioned the deficiencies in the prior art, there is provided one kind is without using expensive trimethyl chloromethyl base silicon
Alkane, to prepare cost low, do not use grignard reaction, without anhydrous and oxygen-free condition, it is easily operated, easily realize industrialized production, and after
Processing is simple, the synthetic method of 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates easy to operate.
In order to solve the above-mentioned technical problem, the technical solution adopted by the present invention is：A kind of 2- [2- (2,4- difluorophenyl) alkene
Propyl group] -1,3- diethyl malonates synthetic method, it is as follows the step of the synthetic method：
(1) 2- chloromethyls expoxy propane (epoxychloropropane) and 1,3- difluorobenzenes are mixed, entered in the presence of catalyst
Row reaction, obtains the chloro- 3- propyl alcohol of 2- (2,4- difluorophenyl) -1-；
(2) step (1) is obtained into the chloro- 3- propyl alcohol of 2- (2,4- difluorophenyl) -1- and potassium acid sulfate and chlorobenzene hybrid reaction,
Obtain 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes；
(3) 1- (1- chloromethyl vinyls base) -2, the 4- difluorobenzenes that step (2) obtains are carried out with diethyl malonate anti-
Should, obtain target product 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates.
The synthetic method of above-mentioned 2- [2- (2,4- difluorophenyl) pi-allyl] -1, the 3- diethyl malonates of the present invention, tool
The synthesis path of body is：
The synthetic method of above-mentioned 2- [2- (2,4- difluorophenyl) pi-allyl] -1, the 3- diethyl malonates of the present invention, step
(1) it is specially：2- chloromethyls expoxy propane and 1,3- difluorobenzene are well mixed at 4~-5 DEG C, then while stirring in batches
Catalyst is added, reacts 5-12 hours after adding at room temperature；Then reaction system is warming up to 45-70 DEG C and continues to react 2-4 hours；
After completion of the reaction, reaction system mixture is added in hydrochloric acid solution at 4~-5 DEG C, made after stirring with dichloromethane
Extracted 2-4 times for extractant, merge the dichloromethane layer extracted every time, then use saturation NaHCO successively3Solution, water, saturation food
Salt water washing；The organic layer (dichloromethane layer) of acquisition uses anhydrous Na2SO4Filtered after drying, oily production is obtained after removing dichloromethane
The chloro- 3- propyl alcohol of thing 2- (2,4- difluorophenyl) -1-.
The mol ratio of 2- chloromethyls expoxy propane, 1,3- difluorobenzenes and catalyst is in step (1) of the present invention：1~1.2:
1:1~1.2；Preferably 1:1:1；Catalyst can be one kind in the lewis acids such as alchlor, zinc chloride, ferric trichloride,
It can also be the concentrated sulfuric acid.
Catalyst is added portionwise can be divided into 3-6 crowd and add described in specific steps (1) of the present invention, the operation can have
Effect prevents that reactant mixture is excessively sticky, it is difficult to the appearance for the problems such as stirring.
Hydrochloric acid solution is the hydrochloric acid solution of 2mol/l concentration in specific steps (1) of the present invention, and the dosage of hydrochloric acid solution is with 2-
Chloromethyl expoxy propane meter, molar concentration of the 2- chloromethyl expoxy propane in hydrochloric acid solution be 0.05-0.2mol/100ml (i.e.
100ml hydrochloric acid solutions correspond to 0.05-0.2mol 2- chloromethyls expoxy propane), preferably 0.1mol/100ml.
Each extraction quantity of dichloromethane and the volume ratio of hydrochloric acid solution are 1.5-2.5 in specific steps (1) of the present invention:3,
Preferably 2:3, such as, if employing the hydrochloric acid solution of 300ml, 2mol/l concentration, each extraction of follow-up dichloromethane
Measure as 200ml.
The synthetic method of above-mentioned 2- [2- (2,4- difluorophenyl) pi-allyl] -1, the 3- diethyl malonates of the present invention, step
(2) it is specially：The chloro- 3- propyl alcohol of 2- (2,4- difluorophenyl) -1- prepared by step (1) and potassium acid sulfate are added in chlorobenzene,
It is heated to reflux 8-15 hours；Chlorobenzene layer is washed to neutrality after completion of the reaction, then uses anhydrous Na2SO4Filtered after drying, filtrate is removed
Oil product 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes are obtained after falling (as being evaporated under reduced pressure) chlorobenzene.
In specific steps (2) of the present invention, the mol ratio of the chloro- 3- propyl alcohol of 2- (2,4- difluorophenyl) -1- and potassium acid sulfate is
1:1-1.5 preferably 1:1.1.
In specific steps (2) of the present invention, molar concentration of the chloro- 3- propyl alcohol of 2- (2,4- difluorophenyl) -1- in chlorobenzene is
(i.e. 300ml chlorobenzenes correspondingly add the 0.15-0.30mol chloro- 3- of 2- (2,4- difluorophenyl) -1- to 0.15-0.30mol/300ml
Propyl alcohol)；Preferably 0.2mol/300ml.
The synthetic method of above-mentioned 2- [2- (2,4- difluorophenyl) pi-allyl] -1, the 3- diethyl malonates of the present invention, step
(3) it is specially：1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes prepared by step (2) are taken and are dissolved in DMSO (dimethyl Asias
Sulfone) in, then add diethyl malonate and hydroxide, the stirring reaction 4-10 hours at 15-35 DEG C；Then water is added,
And gained mixture is stirred into 0.5-1.5 hours, thus obtained solution is extracted first with extractant, at 25-30 DEG C；
The water layer separated after extraction carries out second with extractant, at 25-30 DEG C and extracted；Merge the organic layer extracted twice (to extract
Layer where agent), then washed with sodium hydrate aqueous solution, be then washed with water, distill the solvent under reduced pressure of organic layer after washing
Obtain oily target product 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates.
1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes and DMSO amount ratios are 30-75g in step (3) of the present invention：
100ml；1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes：Hydroxide：The mol ratio of diethyl malonate is 1.0：1.5-
3.0：1.0-4.0 preferable 1.0：2-2.5：3-4.0.
In step (3) of the present invention at 25-30 DEG C stirring reaction 4-6 hours；Then water is added, the addition of water now
It is 2-6 with DMSO volume ratios：1, be preferably:3:1.
Hydroxide can be one kind in potassium hydroxide, cesium hydroxide, lithium hydroxide etc. in step (3) of the present invention.
Extractant can be dichloromethane in step (3) of the present invention, (60-90 DEG C, wherein 60-90 DEG C refers to petroleum ether
The specification of petroleum ether), chloroform, one kind in n-hexane or hexamethylene etc..
Extractant, the extractant of second of extraction and the DMSO volume ratios that step (3) of the present invention extracts first are 2:1:1.
The sodium hydrate aqueous solution concentration of step (3) of the present invention is 5% (weight/volume)；Sodium hydrate aqueous solution and
DMSO volume ratios are 1-3:1.
The advantages of the present invention：
1. present invention use creative first by 2- chloromethyls expoxy propane and 1,3- difluorobenzene as raw material, in two steps
Prepare 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes；Then target product is obtained by simple substitution reaction；The preparation
Process neither uses expensive trimethyl chloromethyl base silane class material, so as to sufficiently lower production cost；And prepare
Technique is more gentle, easily operated, the anhydrous and oxygen-free condition needed without traditional handicraft grignard reaction, more easily operates, and holds
Easily realize industrialized production；In addition, the preparation process does not use the compound chloracetyl chloride of intense irritation yet, so as to reduce ring
Pollute the health influence effectively reduction compared with and by experimenter in border.
2. product prepared by the present invention, post processing is simple, it is thus only necessary to extracts, washs, is evaporated under reduced pressure, you can obtains final
Product, high income；It is applied widely and the material such as the extractant used and hydroxide is easy to get, is cheap.
Embodiment
The present invention is described in further detail below by embodiment, but the present invention is not limited solely to following examples.
Embodiment 1
1st, by 2- chloromethyls expoxy propane (27.60g, 0.30mol) and 1,3- difluorobenzenes (34.23g, 0.30mol) at 0 DEG C
Divide 5 batches to add alchlors (40.00g, 0.30mol) altogether after being well mixed down while stirring, it is small to react 7.5 after adding at room temperature
When, then it is warming up to 58 DEG C and continues reaction 3 hours.Mixture is carefully added into 300ml concentration at 0 DEG C after completion of the reaction
In 2mol/l hydrochloric acid solution, to be extracted three times with dichloromethane after stirring, each 200ml, combined dichloromethane layer, two
Chloromethanes layer uses saturation NaHCO successively3Solution, water, saturated aqueous common salt washed once respectively.Dichloromethane layer nothing after washing
Water Na2SO4Filtered after drying, rotary evaporation obtains the chloro- 3- third of oil product 2- (2,4- difluorophenyl) -1- after removing dichloromethane
Alcohol 51.65g (0.25mol), yield 83%.
2nd, by the chloro- 3- propyl alcohol 41.32g (0.20mol) of 2- (2,4- difluorophenyl) -1-, potassium acid sulfate 29.96g
(0.22mol) is added in 300ml chlorobenzenes, is heated to reflux 14 hours.Chlorobenzene layer is washed to neutrality after completion of the reaction, anhydrous
Na2SO4Filtered after drying, vacuum distillation obtains oil product 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes after removing chlorobenzene
32.06g (0.17mol), yield 85%.
3rd, 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes 37.72g (0.20mol) is taken to be dissolved in 100ml dimethyl sulfoxide (DMSO)s,
12.00g (0.30mol) sodium hydroxides and 90.5ml (0.60mol) diethyl malonate are subsequently added into, reactant mixture is in room temperature
Under (15-35 degrees Celsius) stir 8 hours.300ml water is added after completion of the reaction, continues stirring 1 hour.Resulting solution is used respectively
200ml and 100ml hexamethylenes are extracted twice (being the water layer obtained after extraction extracts for the first time for the second time), merge extraction twice and obtain
The hexamethylene layer (i.e. layer where extractant) obtained, washed once, then use with 150ml 5% (w/v) sodium hydroxide solution
150ml water washings once, anhydrous Na2SO4Filtered after drying, rotary evaporation removes hexamethylene and obtains oil product 2- [2- (2,4- bis-
Fluorophenyl) pi-allyl] -1,3- diethyl malonates 56.22g (0.18mol), yield 90%.
Embodiment 2
1st, by 2- chloromethyls expoxy propane (22.08g, 0.24mol) and 1,3- difluorobenzenes (22.82g, 0.20mol) at 0 DEG C
Divide 4 batches to add ferric trichlorides (0.24mol) altogether after being well mixed down while stirring, reacted at room temperature after adding 8 hours, Ran Housheng
Temperature continues reaction 3 hours to 60 DEG C.It is 2mol/l's that mixture is carefully added into 200ml concentration at 0 DEG C after completion of the reaction
In hydrochloric acid solution, after stirring with dichloromethane extraction three times, each 130ml, combined dichloromethane layer, with saturation NaHCO3
Solution, water, saturated aqueous common salt washed once respectively.Organic layer anhydrous Na2SO4Filtered after drying, rotary evaporation removes dichloromethane
The chloro- 3- propyl alcohol 33.06g of oil product 2- (2,4- difluorophenyl) -1-, (0.16mol), yield 80% are obtained after alkane.
2nd, by the chloro- 3- propyl alcohol 41.32g (0.20mol) of 2- (2,4- difluorophenyl) -1-, potassium acid sulfate 29.96g
(0.22mol), it is added in 200ml chlorobenzenes, is heated to reflux 14 hours.Chlorobenzene layer is washed to neutrality after completion of the reaction, anhydrous
Na2SO4Filtered after drying, vacuum distillation obtains oil product 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes after removing chlorobenzene
32.06g (0.17mol), yield 85%.
3rd, 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes 37.72g (0.20mol) is dissolved in 100ml dimethyl sulfoxide (DMSO)s,
The lithium hydroxide and 90.5ml (0.60mol) diethyl malonate, reactant mixture for being subsequently added into 0.30mol are stirred at room temperature
8 hours.300ml water is added after completion of the reaction, continues stirring 1 hour.Resulting solution uses 200ml and 100ml petroleum ethers respectively
(60-90 DEG C) is extracted twice, and is merged petroleum ether layer, be washed once with 150ml 5% (w/v) sodium hydroxide solution, then
With 150ml water washings once, anhydrous Na2SO4Filtered after drying, rotary evaporation removes petroleum ether and obtains oil product 2- [2- (2,4-
Difluorophenyl) pi-allyl] -1,3- diethyl malonates 56.21g (0.18mol), yield 90%.
It was found from above-described embodiment, method reaction product of the invention is easily operated, and post processing is simple, is easy to industrial metaplasia
Production.
Claims (10)
- A kind of 1. synthetic method of 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates, it is characterised in that：Step Suddenly include：(1) 2- chloromethyls expoxy propane and 1,3- difluorobenzene are mixed, reacted in the presence of catalyst, acquisition 2- (2, 4- difluorophenyls) the chloro- 3- propyl alcohol of -1-；(2) step (1) is obtained into the chloro- 3- propyl alcohol of 2- (2,4- difluorophenyl) -1- and potassium acid sulfate and chlorobenzene hybrid reaction, obtained 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes；(3) 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes that step (2) obtains are reacted with diethyl malonate, obtained Obtain target product 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates；Described catalyst is alchlor, zinc chloride, ferric trichloride or the concentrated sulfuric acid.
- 2. the synthesis side of 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates according to claim 1 Method, it is characterised in that：Specifically synthesis path is：
- 3. the synthesis side of 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates according to claim 1 Method, it is characterised in that：Step (1) is specially：2- chloromethyls expoxy propane and 1,3- difluorobenzene are mixed at 4~-5 DEG C It is even, catalyst is then added portionwise while stirring, reacts 5-12 hours after adding at room temperature；Then reaction system is warming up to 45- 70 DEG C are continued to react 2-4 hours；After completion of the reaction, reaction system mixture is added in hydrochloric acid solution at 4~-5 DEG C, stirred Extracted 2-4 times by the use of dichloromethane as extractant after mixing uniformly, merge the dichloromethane layer extracted every time, then use saturation successively NaHCO3Solution, water, saturated common salt water washing；The organic layer (dichloromethane layer) of acquisition uses anhydrous Na2SO4Filter, remove after drying The chloro- 3- propyl alcohol of oil product 2- (2,4- difluorophenyl) -1- is obtained after falling dichloromethane.
- 4. the synthesis side of 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates according to claim 3 Method, it is characterised in that：The mol ratio of 2- chloromethyls expoxy propane, 1,3- difluorobenzenes and catalyst is 1~1.2 in step (1):1: 1~1.2；Catalyst is divided into 3-6 batches and added.
- 5. the synthesis side of 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates according to claim 3 Method, it is characterised in that：Hydrochloric acid solution is the hydrochloric acid solution of 2mol/l concentration in step (1), and the dosage of hydrochloric acid solution is with 2- chloromethanes Basic ring Ethylene Oxide meter, molar concentration of the 2- chloromethyl expoxy propane in hydrochloric acid solution are 0.05-0.2mol/100ml；Step (1) extraction quantity of each dichloromethane and the volume ratio of hydrochloric acid solution are 1.5-2.5 in:3.
- 6. the synthesis side of 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates according to claim 1 Method, it is characterised in that：Step (2) is specially：The chloro- 3- propyl alcohol of 2- (2,4- difluorophenyl) -1- and sulfuric acid prepared by step (1) Hydrogen potassium is added in chlorobenzene, is heated to reflux 8-15 hours；Chlorobenzene layer is washed to neutrality after completion of the reaction, then uses anhydrous Na2SO4 Filtered after drying, filtrate obtains oil product 1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes after removing chlorobenzene.
- 7. the synthesis side of 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates according to claim 6 Method, it is characterised in that：The mol ratio of the chloro- 3- propyl alcohol of 2- (2,4- difluorophenyl) -1- and potassium acid sulfate is 1 in step (2):1- 1.5；Molar concentration of the chloro- 3- propyl alcohol of 2- (2,4- difluorophenyl) -1- in chlorobenzene is 0.15-0.30mol/ in step (2) 300ml。
- 8. the synthesis side of 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates according to claim 1 Method, it is characterised in that：Step (3) is specially：1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes prepared by step (2) are taken molten Then solution adds diethyl malonate and hydroxide, the stirring reaction 4-10 hours at 15-35 DEG C in dimethyl sulfoxide (DMSO)； Then water is added, and gained mixture is stirred into 0.5-1.5 hours, is entered by thus obtained solution extractant, at 25-30 DEG C Row extracts first；The water layer separated after extraction carries out second with extractant, at 25-30 DEG C and extracted；What merging extracted twice has Machine layer, is then washed with sodium hydrate aqueous solution, is then washed with water, and distills to obtain oil by the solvent under reduced pressure of organic layer after washing Shape target product 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates.
- 9. the synthesis side of 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates according to claim 8 Method, it is characterised in that：1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes and dimethyl sulfoxide (DMSO) amount ratio are 30- in step (3) 75g：100ml；1- (1- chloromethyl vinyls base) -2,4- difluorobenzenes：Hydroxide：The mol ratio of diethyl malonate is 1.0： 1.5-3.0：1.0-4.0.
- 10. the synthesis side of 2- [2- (2,4- difluorophenyl) pi-allyl] -1,3- diethyl malonates according to claim 9 Method, it is characterised in that：In step (3) at 25-30 DEG C stirring reaction 4-6 hours, then add water, the addition of water now It is 2-6 with dimethyl sulfoxide (DMSO) volume ratio：1；Hydroxide is one in potassium hydroxide, cesium hydroxide, lithium hydroxide in step (3) Kind；Extractant is one kind in dichloromethane, petroleum ether, chloroform, n-hexane or hexamethylene in step (3)；Step (3) Sodium hydrate aqueous solution concentration is 5% weight/volume；Sodium hydrate aqueous solution and DMSO volume ratios are 1-3:1.
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| CN105755060A (en) * | 2016-03-30 | 2016-07-13 | 浙江大学宁波理工学院 | Synthesis method for 2-methylpropionate-[(2S)-4-(2,4-difluorophenyl)-2-hydroxymethyl-4-pentene-1-yl]ester |
| CN105777486A (en) * | 2016-03-30 | 2016-07-20 | 浙江大学宁波理工学院 | Synthesis method of 2-[2-(2,4-diflurophenyl)-2-propen-1-yl)-1,3-propanediol |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1147807A (en) * | 1994-05-09 | 1997-04-16 | 先灵公司 | Process for preparing intermediates for the synthesis of antifungal agents |
| CN105622413A (en) * | 2016-01-14 | 2016-06-01 | 宁波新凯生物科技有限公司 | Synthesis method of diethyl 2-[2-(2,4-difluorophenyl)allyl]-1,3-malonate |
| CN105755060A (en) * | 2016-03-30 | 2016-07-13 | 浙江大学宁波理工学院 | Synthesis method for 2-methylpropionate-[(2S)-4-(2,4-difluorophenyl)-2-hydroxymethyl-4-pentene-1-yl]ester |
| CN105777486A (en) * | 2016-03-30 | 2016-07-20 | 浙江大学宁波理工学院 | Synthesis method of 2-[2-(2,4-diflurophenyl)-2-propen-1-yl)-1,3-propanediol |
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